This application requests competitive renewal of a project designed to examine genetic mechanisms underlying the initiation and progression of exocrine pancreatic cancer, one of the most lethal of human neoplasms. The principal objective in this project is to equate the presence of specific genetic alterations (oncogene activation, tumor suppressor gene loss) with specific phenotypic changes in mouse pancreatic ductal epithelial cells;heretofore it has not been possible to selectively target this cell type. This is accomplished using genetically engineered mouse models. To provide relevance to the human disease, the evaluated genetic alterations are those most often identified in human pancreatic cancers. Finally, phenotypic characterization examines endpoints that are of direct clinical relevance--lesion latency, multiplicity, histotype, and behavior, e.g., invasiveness and metastasis. This approach is important because cancer is a clinical disease only in the context of a patient (animal or human), in which complex growth-regulatory homeostatic mechanisms are active. Clinical endpoints, therefore, provide the information needed to make decisions about patient prognosis and treatment once that patient's cancer has been evaluated at the molecular level. This proposal has the following Aims. Specific Aim 1: Create mouse models of primary pancreatic ductal cancer. Working hypothesis: When mutant Kras is expressed in mouse pancreatic ductal epithelium, the pancreatic lesions that develop will be preinvasive ductal carcinoma in situ, reflecting a role for mutant Kras in an early Stage of pancreatic cancer development. Specific Aim 2: Establish the relationship between Kras mutation and pancreatic cancer initiation, persistence, and progression. Working hypotheses: (1) mutations in Kras will act synergistically with loss of p53, p16, and/or Smad4 to accelerate ductal pancreatic cancer progression;and (2) maintenance of mutant Kras-induced pancreatic ductal lesions requires continued ras expression. Specific Aim 3: Define the causal link between erbB2 overexpression and pancreatic cancer. Working hypotheses: (1) erbB2 overexpression in pancreatic ductal epithelium is not sufficient to induce pancreatic neoplasia, but (2) it will act synergistically with a subset of other genetic alterations - expression of mutant Kras, loss of p53, p16, and/or Smad4 - to accelerate pancreatic carcinogenesis.